The present invention is directed to a process for the preparation of (+)-(2R)-endo-norborneol and (-)-(2S)-endo-norborneol, and for their further conversion, respectively, to the pharmaceutical agents 5- ( 3 -[(2S) -exo-bicyco[2.2.1 ]hept- 2-yloxy ]-4 -methoxy-phenyl) -3,4,5,6-tetrahydropyrimidin-2(1H) -one, of the formula ##STR3## and its enantomer, 5-(3-[2R) -exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimi din-2(1H)-one, of the formula ##STR4## The present invention is also directed to these particular optically active pharmaceutical agents per se, and to intermediates [of the formulas (III) to (VI) below] used in their synthesis.
(2R)-endo-Norborneol is alternatively named (2R)-endo-bicyclo[2.2.1]heptan-2-ol or (1S,2R,4R)bicyclo[2.2.1]heptan-2-ol. Likewise, enantiomeric (2S)-endo-norborneol is alternatively named (2S)-endobicyclo [2.2.1 ]heptan-2-ol or ( 1R, 2S, 4S) -bicyclo [2.2.1 ]-heptan-2-ol. Analogously, derived ( 2S ) -exo-bicyclo[2.2.1 ]hept-2-yl and (2R) -exo-bicyclo [2.2.1 ]hept-2-yl substituent groups are alternatively named, respectively, (1S,2S,4R)-bicyclo[2.2.1]hept-2-yl and ( 1R, 2R, 4S) -bicyclo [2.2.1 ]hept-2-yl.
The present compounds of the formulas (I) and (II) represent particularly valuable species of the compounds broadly disclosed by Saccomano, et al. in published International Patent Application W087/06576, having utility as antidepressants. Although that reference specifically discloses racemic 5-(3-exo-bicyclo [2.2.1 ]hept-2-yloxy]-4-methoxyphenyl)- 3,4,5,6-tetrahydropyrimidin-2 (1H) -one, there is no specific disclosure of the present optically active variants thereof, or of any specific method for their preparation.
Heretofore, optically active (2R)-and (2S)-endo-norborneols were obtained by resolution of racemic exo-norborneol hemiphthalate ester with optically active phenethylamines, hydrolysis to optically active exo-norborneols, CrO.sub.3 oxidation to optically active norbornanones and finally Li(s-Bu).sub.3 BH reduction to the desired endo-isomers. Irwin et al., J. Am. Chem. Soc., v. 98, pp. 8476-8481 (1979). According to the same reference, enantomeric enrichment of endo-norborneols was achieved by incomplete horse liver alcohol dehydrogenase catalyzed reduction of racemic 2-norbornanone; while incomplete oxidation of racemic exo-norborneol catalyzed by the same enzyme gave enantiomerically enriched exo-norborneols. (-)-exo-Norborneol has also been prepared from norbornene by asymmetric hydroboration, Brown, et al., J. Org. Chem, v. 47, pp. 5065-5069 (1982).
Heretofore, certain chiral alcohols have been resolved using transesterification catalyzed by porcine pancreatic lipase in a nearly anhydrous organic solvent. Kirchner, et al., J. Am. Chem. Soc. v. 107, pp. 7072-7076 (1985). For example, 47% conversion of racemic 2-octanol and 2,2,2-trichloroethyl butyrate gave (R)-2-octyl butyrate of high optical purity. However, when this method was applied to racemic exo-norborneol, both the recovered alcohol and the product butyrate ester remained essentially racemic, even though the transesterification was definitely enzyme mediated (as shown by lack of reaction absent the enzyme).